Treating critically ill patients with intravenous ibuprofen

ABSTRACT

Methods of treating at least one condition chosen from pain, inflammation, and fever in a critically ill patient in need thereof, comprising administering to the critically ill patient an intravenous pharmaceutical composition comprising ibuprofen using a first dosage regimen, wherein the first dosage regimen produces a first pharmacokinetic profile in critically ill patients that is about equivalent to a second pharmacokinetic profile produced by administration of the intravenous pharmaceutical composition using a second dosage regimen of ibuprofen to non-critically ill patients, wherein the at least one condition of the critically ill patient is thereby treated.

This application is a continuation application of U.S. Ser. No.12/646,499, filed Dec. 23, 2009, which claims the benefit under 35U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/230,324,filed Jul. 31, 2009, the entire disclosure of which is herebyincorporated herein by reference for all purposes. This application alsoclaims benefit of priority under 35 U.S.C. §120 to U.S. patentapplication Ser. No. 12/570,912, filed Sep. 30, 2009, the entiredisclosure of which is hereby incorporated herein by reference for allpurposes.

Provided are methods for treating critically ill patients byintravenously administering a pharmaceutical composition comprising aneffective amount of 2-(4-isobutylphenyl) propionic acid.

2-(4-isobutylphenyl) propionic acid, whose International NonproprietaryName is ibuprofen, is a well-known anti-inflammatory drug having amolecular weight of 206.28 and the following chemical structure:

(Merck Index 12th ed., n4925, page 839). Originally patented in the1960's, ibuprofen is now marketed generically, as well as under thetradenames of Motrin®, Advil®, and Nuprin® for the treatment of pain,inflammation, and fever. The U.S. Food and Drug Administration recentlyapproved a new formulation of ibuprofen for intravenous administrationto be marketed under the trade name Caldolor®.

Ibuprofen is readily available as the racemic mixture ((RS)-Ibuprofen)of the two enantiomers, (R)-Ibuprofen and (S)-Ibuprofen. Even though the(S) enantiomer is the biologically active form, most preparationscontain the racemic mixture since the (R) enantiomer is converted to theactive (S) form in-vivo. For simplicity, hereinafter the term“ibuprofen” will be used to indicate any one of the (R) enantiomer, the(S) enantiomer, or the racemate.

Although ibuprofen has many advantages over other analgesics such asaspirin and acetaminophen, it is very poorly soluble in water. Thus,certain dosage forms of ibuprofen, especially injectable liquids, havebeen difficult to develop. Several U.S. patents have addressed thisproblem.

For example, U.S. Pat. No. 4,309,421 appears to describe water-solublecomplexes of ibuprofen and phospholipids suitable for parenteraladministration. U.S. Pat. Nos. 4,859,704 and 4,861,797 appear todescribe the synthesis of alkali metal salts of ibuprofen for preparinga liquid ibuprofen formulation.

Other U.S. patents appear to address this problem by preparing anibuprofen salt with a basic amino acid as the active pharmaceuticalingredient and then solubilizing the salt to produce a liquid dosageform.

For example, U.S. Pat. No. 5,200,558 appears to describe enhancedanalgesic effects of S (+) ibuprofen as salts of L and D amino acids,including arginine, in various dosage forms, including as an injectablesolution. U.S. Pat. No. 4,279,926 appears to describe the use of basicamino acid salts of propionic acids for relieving pain and treatinginflammatory conditions. Similarly, U.S. Pat. No. 5,463,117 appears todescribe the preparation of salts of ibuprofen with basic amino acids.Finally, U.S. Pat. No. 6,005,005 appears to describe a liquidcomposition for oral use containing ibuprofen and arginine.

U.S. Pat. No. 6,727,286 B2 describes, among other things, apharmaceutical composition comprising an aqueous solution of arginineand ibuprofen, wherein the molar ratio of arginine to ibuprofen is lessthan 1:1, as well as a method of making the same. That patent alsoprovides a method of treating a condition chosen from pain,inflammation, fever, and/or other conditions alleviated by ibuprofencomprising administering a pharmaceutical composition comprising anaqueous solution of arginine and ibuprofen, wherein the molar ratio ofarginine to ibuprofen is less than 1:1. The entire contents of U.S. Pat.No. 6,727,286 B2 are hereby incorporated herein by reference.

The U.S. Food and Drug Administration recently approved a newformulation of ibuprofen for intravenous administration to be marketedunder the trade name Caldolor® by Cumberland Pharmaceuticals, Inc.Caldolor® contains the active ingredient ibuprofen. As described on thelabeling for Caldolor®, “each 1 mL of solution contains 100 mg ofibuprofen in Water for Injection, USP. The product also contains 78mg/mL arginine at a molar ratio of 0.92:1 arginine:ibuprofen. Thesolution pH is about 7.4.” Caldolor® is sterile and is intended forintravenous administration only.

Caldolor® possesses antiinflammatory, analgesic, and antipyreticactivity. As such, Caldolor® is indicated in adults for the managementof mild to moderate pain and the management of moderate to severe painas an adjunct to opioid analgesics. 400 mg to 800 mg of Caldolor® isadministered intravenously every 6 hours as necessary to treat pain.Caldolor® is also indicated for the reduction of fever in adults. 400 mgof Caldolor® is administered intravenously, followed by 400 mg every 4to 6 hours or 100-200 mg every 4 hours as necessary to treat fever.

SUMMARY OF THE INVENTION

Provided are methods of treating at least one condition chosen frompain, inflammation, and fever in a critically ill patient in needthereof. The methods include administering to the critically ill patientan intravenous pharmaceutical composition comprising ibuprofen using afirst dosage regimen, wherein the first dosage regimen produces a firstpharmacokinetic profile in critically ill patients that is aboutequivalent to a second pharmacokinetic profile produced byadministration of the intravenous pharmaceutical composition using asecond dosage regimen of ibuprofen to non-critically ill patients,wherein the at least one condition of the critically ill patient isthereby treated.

In some embodiments the first dosage regimen includes administration ofat least one dose of ibuprofen that is higher than any dose of ibuprofenadministered in the second dosage regimen. In some embodiments the firstdosage regimen comprises a dosing interval that is shorter than anydosing interval used in the second dosage regimen. In some embodimentsthe first pharmacokinetic profile produced by administration of thefirst dosage regimen of ibuprofen to critically ill patients includes anarea under plasma concentration-time curve (AUC) over a period of timethat is about equivalent to the AUC over the period of time of thesecond pharmacokinetic profile produced by administration of the seconddosage regimen of ibuprofen to non-critically ill patients.

In some embodiments the first dosage regimen includes administration ofa dose of ibuprofen of greater than a dose administered tonon-critically ill patients in a second dosage regimen, wherein the doseadministered in the first dosage regiment is from 100 to 1600 mg. Insome embodiments the dose administered in the first dosage regimen isselected from 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg,450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 800 mg, 1000 mg, 1200mg, 1400 mg, 1600 mg, 2400 mg, and 3200 mg. In some embodiments the doseadministered in the first dosage regimen is selected from 100 mg, 200mg, 400 mg, and 800 mg.

In some embodiments the first dosage regimen includes a dosing intervalthat is shorter than any dosing interval used in the second dosageregimen. In some embodiments the at least one condition is pain. In someembodiments the at least one condition is inflammation. In someembodiments the at least one condition is fever.

In some embodiments the critically ill patient is a patient receiving atleast one form of treatment selected from treatment with a vasopressorand mechanical ventilation.

In some embodiments the pharmaceutical composition is an aqueoussolution of arginine and ibuprofen.

In some embodiments the molar ratio of arginine to ibuprofen is selectedfrom less than or equal to 1:1, less than or equal to 0.99:1, less thanor equal to 0.98:1, less than or equal to 0.97:1, less than or equal to0.96:1, less than or equal to 0.95:1, less than or equal to 0.94:1, lessthan or equal to 0.93:1, less than or equal to 0.92:1, less than orequal to 0.91:1, less than or equal to 0.90:1, less than or equal to0.60:1. In some embodiments the pharmaceutical composition is Caldolor®.

In some embodiments administering the first dosage regimen to criticallyill patients reduces the at least one condition chosen from pain,inflammation, and fever to an about equivalent extent to the reductionof the at least one condition chosen from pain, inflammation, and feverachieved in non-critically ill patients to which the second dosageregimen is administered.

The invention is further directed to a method of treating at least onecondition chosen from pain, inflammation, and fever in critically illpatients in need thereof, comprising administering to the critically illpatient an intravenous ibuprofen pharmaceutical composition in a dosefrom about 400 mg to about 800 mg every 4 to 6 hours, to attain a meanCmax of about 20.8 μg/ml to about 75 μg/ml.

In certain preferred embodiments, the method further comprisesadministering to the critically ill patient an intravenous ibuprofenpharmaceutical composition in a dose from about 400 mg to about 800 mgevery 4 to 6 hours, to attain a mean AUC of about 36.8 μg.h/ml to about117.5 μg.h/ml.

The invention is further directed to a method of treating at least onecondition chosen from pain, inflammation, and fever in critically illpatients in need thereof, comprising administering to the critically illpatients an intravenous ibuprofen pharmaceutical composition in anamount sufficient to attain a desired Cmax and AUC for those patients,wherein the dose of intravenous ibuprofen administered to the criticallyill patients is about twice the dose of intravenous ibuprofen thatprovides a substantially equivalent Cmax and AUC when administered tonon-critically ill patient population, such that the dose reduces atleast one condition chosen from pain, inflammation, and fever in thecritically ill patient.

As used herein the term “treat,” “treating” or “treatment” refers to theadministration of ibuprofen to an individual who already manifests, hasin the past manifested, and/or is at risk of manifesting at least onesymptom of a disease or condition, that can be reduced or alleviated byadministration of ibuprofen. Examples of such diseases and conditionsinclude pain, inflammation, and fever.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows mean ibuprofen plasma concentrations (hours 0-4) followingadministration of 100 mg IVIb in critically ill versus non-criticallyill patients.

FIG. 2 shows mean ibuprofen plasma concentrations (hours 0-4), followingadministration of 200 mg IVIb in critically ill versus non-criticallyill patients.

FIG. 3 shows mean ibuprofen plasma concentrations (hours 0-4) followingadministration of 400 mg IVIb in critically ill versus non-criticallyill patients.

FIG. 4 shows temperature over time by stratum, 400 mg IVIb vs. placebo.

FIG. 5 shows the difference in mean temperature in critically illpatients in Example 3 for IVIb versus placebo.

Provided herein are methods of treating at least one condition chosenfrom pain, inflammation, and fever in a critically ill patient in needthereof.

DETAILED DESCRIPTION OF THE INVENTION

In some embodiments a “critically ill” patient is a patient receiving atleast one of vasopressor support and mechanical ventilation. In anotherembodiment of the invention a “critically ill” patient is at least oneof a patient receiving vasopressor support, receiving mechanicalventilation, being treated in an Intensive Care Unit (“ICU”), e.g., of ahospital, being administered large volumes of blood products, especiallypacked red cells, undergoing dialysis, especially continuous veno-venoushemofiltration, receiving multiple antibiotics, having a pulmonaryartery catheter and having an arterial blood pressure catheter inserted.These criteria for critically ill patients are exemplary only, and oneskilled in the art will understand that other indicia of a patient in acritically ill state are possible and are considered to be encompassedby the term “critically ill” as it is used herein. As used herein apatient receiving “vasopressor support” refers to a patient unable tomaintain a sufficient blood pressure who is consequently being treatedwith a vassopressor to raise the patient's bloodpressure. Examples ofvasopressor support medications include Norepinephrine (marketed forexample under the brand name Levophed®).

Certain methods described herein comprise administering to thecritically ill patient an intravenous pharmaceutical compositioncomprising ibuprofen. Intravenous pharmaceutical compositions ofibuprofen include any formulation suitable for administration to apatient via any intravenous method, including a bolus. In someembodiments the rate of infusion is such that the dose is administeredover a period of about 30 minutes. In some embodiments the rate ofinfusion is such that the dose is administered over a period of lessthan 30 minutes. In some embodiments the rate of infusion is such thatthe dose is administered over a period of greater than 30 minutes.

In alternative embodiments of the treatment methods described herein apharmaceutical formulation comprising ibuprofen is administered to apatient via an injection method. In such embodiments the pharmaceuticalformulation of ibuprofen is a formulation suitable for administration toa patient via the injection method. Suitable injection methods include,in addition to intravenous injection, intraarterial infusion,intramuscular injection, transdermal injection, and subcutaneousinjection.

Suitable carriers for intravenous administration include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingsolubilizing agents, such as glucose, polyethylene glycol, andpolypropylene glycol and mixtures thereof.

The formulation may include an aqueous vehicle. Aqueous vehiclesinclude, by way of example and without limitation, Sodium ChlorideInjection, Ringers Injection, Isotonic Dextrose Injection, Sterile WaterInjection, Dextrose, and Lactated Ringers Injection. Nonaqueousparenteral vehicles include, by way of example and without limitation,fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil andpeanut oil. Antimicrobial agents in bacteriostatic or fungistaticconcentrations must be added to parenteral preparations packaged inmultiple dose containers which include phenols or cresols, mercurials,benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acidesters, thimerosal, benzalkonium chloride and benzethonium chloride.Isotonic agents include, by way of example and without limitation,sodium chloride and dextrose. Buffers include phosphate and citrate.Antioxidants include sodium bisulfate. Local anesthetics includeprocaine hydrochloride. Suspending and dispersing agents include sodiumcarboxymethylcelluose, hydroxypropyl methylcellulose andpolyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN®80). A sequestering or chelating agent of metal ions include EDTA.Pharmaceutical carriers also include, by way of example and withoutlimitation, ethyl alcohol, polyethylene glycol and propylene glycol forwater miscible vehicles and sodium hydroxide, hydrochloric acid, citricacid or lactic acid for pH adjustment.

Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of ibuprofen.

As used herein a “dosage regimen” refers to the protocol used toadminister an intravenous pharmaceutical formulation comprisingibuprofen to a patient. In some embodiments the dosage regimen comprisesa dose amount and dosing interval. In some embodiments the dosageregimen further comprises a dosing duration. As used herein “dosingduration” refers to the period of time over which a dose isadministered. For example, if a volume of pharmaceutical compositioncomprising 400 mg of ibuprofen is administered over a dosing duration of30 min and administration of a dose is initiated every 6 hours, then thedosage regimen is 400 mg, every six hours, administered over 30 minutes.In some embodiments the dosage duration is defined simply as 400 mg,every six hours.

In some embodiments described herein a dosage regimen for critically illpatients is defined as one that produces a first pharmacokinetic profilein critically ill patients that is about equivalent to a secondpharmacokinetic profile produced by administration of a second dosageregimen of ibuprofen to non-critically ill patients. As used herein, twopharmacokinetic profiles are “about equivalent” if they are defined byat least one parameter that is about equivalent between the twoprofiles. Non-limiting examples of such parameters include the areaunder plasma concentration over time curve (AUC) and the maximal plasmaconcentration reached following administration of a dose (Cmax).

In some embodiments two pharmacokinetic parameters are about equivalentif the lower value is greater than 70%, greater than 75%, greater than80%, greater than 85%, greater than 90%, greater than 95%, greater than96%, greater than 97%, greater than 98%, or greater than 99% of thehigher value.

The pharmacokinetic profiles of two dosage regimens are compared bydetermining the average pharmacokinetic profile in a population ofpatients receiving the first dosage regimen, determining the averagepharmacokinetic profile in a population of patients receiving the seconddosage regimen, and then comparing those two population dosage regimens.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The present invention contemplates the use of intravenous formulationsof ibuprofen that are bioequivalent to the Caldolor® formulations andadministrations disclosed herein, as defined by typical FDA criteria. Inparticular, it is contemplated that formulations and methods exhibitingat least one of the Cmax and AUC profiles within 80-125% of the Cmax andAUC values contemplated herein for the administration of intravenousibuprofen (Caldolor®).

Thus, in certain embodiments, the invention is directed to a method oftreating at least one condition chosen from pain, inflammation, andfever in critically ill patients in need thereof receiving, e.g., atleast one of pressor support and mechanical ventilation, comprisingadministering to the critically ill patient an intravenous ibuprofenpharmaceutical composition in a dose from about 400 mg to about 800 mgevery 4 to 6 hours, to attain a mean Cmax of about 20.8 μg/ml to about75 μg/ml. The value of mean Cmax of 20.8 μg/ml is obtained bycalculating 80% of the approximately 26 (25.7) μg/ml Cmax value obtainedin Example 1. The value of mean Cmax of about 75 μg/ml is obtained bytaking 50% of the approximately 120 μg/ml Cmax value surmised fromExamples 2-3 (60 μg/ml), and calculating 125% of that number. (Seeparagraph 075).

In certain preferred embodiments, the method further comprisingadministering to the critically ill patient an intravenous ibuprofenpharmaceutical composition in a dose from about 400 mg to about 800 mgevery 4 to 6 hours, to attain a mean AUC of about 36.8 μg.h/ml to about117.5 μg.h/ml. The value of mean AUC of 36.8 μg.h/ml is obtained bycalculating 80% of the approximately 46 (45.937) μg.h/ml AUC valueobtained in Example 1. The value of mean AUC of 117.5 μg.h/ml isobtained by taking 50% of the approximately 188 μg.h/ml AUC valuesurmised from Examples 2-3 (94 μg.h/ml), and calculating 125% of thatnumber. (See paragraph 075).

The invention is further directed to a method of treating at least onecondition chosen from pain, inflammation, and fever in critically illpatients in need thereof receiving at least one of pressor support andmechanical ventilation, comprising administering to the critically illpatients an intravenous ibuprofen pharmaceutical composition in anamount sufficient to attain a desired Cmax and AUC for those patients,wherein the dose of intravenous ibuprofen administered to the criticallyill patients is about twice the dose of intravenous ibuprofen thatprovides a substantially equivalent Cmax and AUC when administered to anon-critically ill patient population, such that the dose reduces atleast one condition chosen from pain, inflammation, and fever in thecritically ill patient. In certain preferred embodiments of this method,the dose of intravenous ibuprofen administered to the critically illpatients is 200 mg and provides a mean Cmax within about 80% to about125% of 11.5 μg/ml. In certain additional preferred embodiments of thismethod, the dose of intravenous ibuprofen administered to the criticallyill patient is 200 mg and provides a mean (AUC)0-4 within about 80% toabout 125% of 19.6 μg.h/ml. In certain preferred embodiments of thismethod, the dose of intravenous ibuprofen administered to the criticallyill patients is 400 mg and provides a mean Cmax within about 80% toabout 125% of 257 μg/ml. In certain additional preferred embodiments ofthis method, the dose of intravenous ibuprofen administered to thecritically ill patient is 400 mg and provides a mean (AUC)0-4 withinabout 80% to about 125% of 45.9 μg.h/ml. In other embodiments of thismethod, the dose of intravenous ibuprofen administered to the criticallyill patients is 800 mg and provides a mean Cmax within about 80% toabout 125% of 60 μg/ml. In certain additional preferred embodiments ofthis method, the dose of intravenous ibuprofen administered to thecritically ill patients is 800 mg and provides a mean (AUC)0-t withinabout 80% to about 125% of 94 μg.h/ml.

The invention is further directed to a method of treating at least onecondition chosen from pain, inflammation, and fever in critically illpatients in need thereof receiving at least one of pressor support andmechanical ventilation, comprising administering to the critically illpatient an intravenous pharmaceutical composition comprising ibuprofenat a dosage of (i) 100 mg ibuprofen to attain a mean Cmax of about 8.2μg/ml±6.3; or (ii) 200 mg ibuprofen to attain a mean Cmax of about 11.5μg/ml±2.8; or (iii) 400 mg ibuprofen to attain a mean Cmax of about 25.7μg/ml±8.3 or (iv) 800 mg ibuprofen to attain a mean Cmax within 80-125%of about 60 μg/ml. In certain preferred embodiments of this method, thedose of ibuprofen produces a mean area under plasma concentration-timecurve (AUC)0-4 of about 16.1 μg.h/ml±14.6 for a dose of 100 mgibuprofen; a mean area under plasma concentration-time curve (AUC)0-4 ofabout 19.6 μg.h/ml±7.0 for a dose of 200 mg ibuprofen; a mean area underplasma concentration-time curve (AUC)0-4 of about 45.9 μg.h/ml±16.2 fora dose of 400 mg ibuprofen; or a mean area under plasmaconcentration-time curve (AUC)0-4 within 80-125% of about 94 μg.h/ml fora dose of 800 mg ibuprofen.

Further embodiments of the invention are directed to a method oftreating at least one condition chosen from pain, inflammation, andfever in critically ill patients in need thereof receiving at least oneof pressor support and mechanical ventilation, comprising administeringto the critically ill patients an intravenous ibuprofen pharmaceuticalcomposition in an amount sufficient to attain a desired Cmax and AUC forthose patients, wherein the dose of intravenous ibuprofen administeredto the critically ill patients provides a Cmax and AUC which is fromabout 50% to about 61.2% of the Cmax and AUC for that dose ofintravenous ibuprofen when administered to a non-critically ill patientpopulation, such that the dose reduces at least one condition chosenfrom pain, inflammation, and fever in the critically ill patient.

The following example represents specific embodiments of the foregoingdiscovery, and is not representative of the entire scope of theinvention.

Example 1

This study was conducted in hospitalized patients who were stratified byseverity of illness (critically ill vs. non-critically ill). Criticallyill patients were defined as receiving vasopressor support and/ormechanical ventilation. Patients received intravenous ibuprofen(Caldolor®) at the indicated dosages.

To be eligible for this study, the patients in the study met all of thefollowing criteria: be hospitalized; have new (not chronic, within last7 days) onset of fever, documented by temperature greater than or equalto 101.0° F. (38.3° C.) (the preferred method of temperature measurementwas core. If a non-core route was used, temperature measurement shouldhave been verified by an additional route of measurement; the route oftemperature measurement used immediately before randomization was usedimmediately before dosing and for all temperature measurements duringthe treatment period); had adequate intravenous access; and understoodand abided by the study requirements. Randomization was stratified onthe basis of the severity of the patient's condition (critically ill ornon-critically ill), at the time of randomization. At least 33% of thesubjects randomized were to be critically ill (in the hospital requiringmechanical ventilation for respiratory failure, pressor support forhypotension, or both), and at least 33% were to not be critically ill.

The test product, dose and mode of administration was intravenousibuprofen: 100, 200 or 400 mg, intravenous; the reference product, doseand mode of administration was normal saline, 100 ml, intravenous. Theduration of treatment was 6 doses, one dose every 4 hours. Plasmaibuprofen levels were obtained for pharmacokinetic analyses at baselineand hours 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 14, 16, 18, 20,22 and 24 from a subset of subjects (n=98).

Analysis of the data sets assessing the efficacy of intravenousibuprofen (IVIb) for the treatment of fever in non-critically ill andcritically ill hospitalized patients revealed a difference inpharmacokinetics and treatment effect on reduction in temperature. TheCmax and AUC for all doses of IVIb were significantly reduced incritically ill patients when compared to non-critically ill patients,while the pharmacokinetics remained first order in both patientpopulations. Table 1 presents the summary pharmacokinetic parametersdetermined from the patients enrolled in the study, by IVIb dose leveland stratum.

TABLE 1 Summary of Pharmacokinetic Parameters by IVIb Dose Level andStratum AUC₀₋₄ Cmax₀₋₄ Tmax₀₋₄ Cmin_(dose1) Tmin_(dose1) Cmin_(dose6)Tmin_(dose6) Thalf AUC₀₋₄/ Treatment, Stratum (ug · h/mL) (ug/mL) (h)(ug/mL) (ug/mL) (h) (h) (h) Dose 100 mg Critically Ill N 9 9 9 9 9 6 6 69 IVIb Mean 16.101 8.230 0.6 2.193 4.0 2.3 25.7 2.42 161.01 Stdev 14.6386.348 0.2 2.688 0.0 1.8 0.8 1.49 146.38 Min 3.760 3.679 0.5 0.000 4.00.4 24.0 0.19 37.60 Max 50.307 23.839 1.0 8.180 4.0 4.7 26.0 4.79 503.07Non-critically N 14 15 15 14 14 14 14 14 14 Ill Mean 26.328 14.530 0.52.945 4.0 2.6 26.0 2.49 263.28 Stdev 9.954 6.043 0.1 1.166 0.0 1.4 0.01.04 99.54 Min 7.197 5.234 0.5 0.508 4.0 0.3 26.0 1.31 71.97 Max 42.13924.667 1.0 4.416 4.0 5.7 26.0 4.90 421.39 200 mg Critically Ill N 9 9 99 9 9 9 9 9 IVIb Mean 19.615 11.455 0.5 2.293 3.8 1.9 26.0 2.56 98.07Stdev 7.014 2.760 0.0 1.697 0.4 2.1 0.0 1.57 35.07 Min 9.806 7.885 0.50.556 3.0 0.3 26.0 1.26 49.03 Max 30.987 16.390 0.5 5.393 4.0 6.4 26.05.11 154.93 Non-critically N 17 17 17 17 17 17 17 16 17 Ill Mean 39.51022.893 0.5 4.732 3.9 3.0 26.0 1.86 197.55 Stdev 17.383 10.968 0.1 2.7430.2 3.2 0.0 0.53 86.92 Min 9.367 7.788 0.5 0.542 3.0 0.3 26.0 1.23 46.83Max 70.212 49.913 1.0 10.895 4.0 13.7 26.0 3.36 351.06 400 mg CriticallyIll N 10 10 10 10 10 9 9 9 10 IVIb Mean 45.937 25.701 0.5 4.689 3.9 5.026.0 2.32 114.84 Stdev 16.195 8.313 0.0 2.936 0.3 4.3 0.0 0.84 40.49 Min25.753 16.664 0.5 0.850 3.0 2.0 26.0 1.53 64.38 Max 80.147 42.542 0.510.453 4.0 12.7 26.0 4.01 200.37 Non-critically N 15 15 15 15 15 14 1414 15 Ill Mean 87.113 49.128 0.5 10.657 3.8 6.6 26.0 2.22 217.78 Stdev29.188 16.141 0.0 4.822 0.4 5.4 0.0 1.05 72.97 Min 37.351 20.310 0.53.677 3.0 1.7 26.0 1.48 93.38 Max 141.771 72.257 0.5 22.294 4.0 23.826.0 5.54 354.43

FIGS. 1, 2 and 3 present the Cmax graphically for the treatment groups,by stratum.

The efficacy of IVlb for the treatment of fever in the non-criticallyand critically ill patients was examined to better understand theclinical relevance of the pharmacokinetic difference presented in thestudy. FIG. 4 compares the effect of placebo and a 400 mg dose of IVlbon body temperature in non-critically and critically ill hospitalizedpatients. These data suggest that severity of illness appears to lowerCmax and AUC of IVIb which appears to limit the therapeutic effect.

At 4 hours, in the “intention to treat” (ITT) population, 24 of 31 (77%)of subjects in the 400 mg IVIb group, compared to 9 of 28 (32%) of theplacebo group had a temperature less than 101.0° F. (or 38.3° C.),p=0.0005, also clearly demonstrating the efficacy of the 400 mg dose ofIVIb on reducing fever and meeting the primary endpoint.

Further, doses of 100 mg and 200 mg were also found to be statisticallysignificant in reducing fever at the 4 hour primary endpoint.

There were no statistically significant differences between treatmentgroups compared with placebo in terms of adverse event occurrence(limited to events occurring in at least 3 subjects) except forbacteraemia where the incidence was 13% in the 100 mg treatment group(n=4) vs. 0% in the placebo group (p=0.045). There were no statisticallysignificant differences in the occurrence of serious adverse events ordeaths in any treatment group when compared with placebo.

While 400 mg is proposed as the effective dose for the indication ofreduction of fever, a dose adjustment up to 800 mg for the treatment offever may be warranted if the reduction in fever at a lower dose is notadequate. Table 2 presents the percent (%) difference between thecritically ill versus the non-critically ill stratums for the AUC₀₋₄ andCmax₀₋₄ pharmacokinetic parameters.

TABLE 2 Pharmacokinetic Parameters Differences in the 400 mg IVIb DoseLevel and Stratum AUC₀₋₄ Cmax₀₋₄ Treatment, Stratum (ug · h/mL) (ug/mL)100 mg IVIb Critically Ill 16.10 8.23 Non-critically Ill 26.33 14.53Critically Ill/Non-critically Ill 61.2% 56.6% % Difference 200 mg IVIbCritically Ill 19.62 11.46 Non-critically Ill 39.51 22.89 CriticallyIll/Non-critically Ill 49.6% 50.0% % Difference 400 mg IVIb CriticallyIll 45.94 25.70 Non-critically Ill 87.11 49.13 CriticallyIll/Non-critically Ill 52.7% 52.5% % Difference

The values for the AUC and Cmax pharmacokinetic parameters for thecritically ill patients were approximately 50% compared to theparameters for the non-critically ill patients. This difference suggeststhat the dose may need to be increased from 400 mg up to 800 mg fortreatment of fever, depending upon the severity of illness for thepatient being treated.

Based on the overall efficacy and safety results, IVIB appears to beboth safe and effective in reducing fever in both critically ill andnon-critically ill patients.

Example 2

This study was a randomized, double-blind, placebo-controlled, singledose, crossover study of the pharmacokinetics, safety and tolerabilityof ibuprofen injection (IVIb) in healthy adult volunteers. It evaluatedthe pharmacokinetics profile of a single dose of IVIb administered over5-7 minutes.

Twelve subjects were randomized in equal proportion to one of twosequences:

Sequence A: A single dose of IVIb and oral placebo administeredconcurrently on Day 1 of the Treatment Period followed by a single doseof oral ibuprofen and intravenous placebo given concurrently on Day 8 ofthe Treatment Period. Days 2-7 were a washout period.

Sequence B: A single dose of oral ibuprofen and intravenous placeboadministered concurrently on Day 1 of the Treatment Period followed by asingle dose of IVIb and oral placebo given concurrently on Day 8 of theTreatment Period. Days 2-7 were a washout period.

In each Period, subjects received a single dose of ibuprofen 800 mg, asone of:

-   -   8 mL IVIb 100 mg/ml added to 192 mL of normal saline, along with        placebo capsule;    -   800 mg tablet ibuprofen, along with 200 mL of normal saline IV.

The oral dose was administered with approximately 240 ml of water.

Pharmacokinetics parameters in plasma were determined for all 12subjects. Averages (and standard deviations) by treatment of key plasmapharmacokinetics parameters of ibuprofen (IVIb and oral) are provided inTable 3 below:

TABLE 3 C_(max) AUC_(0-tlast) AUC₀₋₁₂ AUC_(0-inf) t_(1/2) Treatment(μg/mL) (h*μg/mL) (h*μg/mL) (h*μg/mL) (h) IVIb 120 (13) 188 (37) 191(36) 196 (37) 2.0 (0.5) Oral  63 (12) 189 (36) 191 (36) 196 (36) 1.9(0.3) Ibuprofen

Median T_(max) was 0.11 hours (6.5 minutes) for IVIb and 1.50 hours fororal ibuprofen.

The comparison between treatments showed that intravenous ibuprofen(IVIb) had equivalent bioavailability to oral ibuprofen, as determinedby the mean ratio of geometric least squares means of AUC0-tlast (meanratio 100%, with 90% confidence interval 90%-112%). The mean Cmax ofIVIb was approximately twice that of the oral dose. The median Tmax ofthe oral dose was 1.50 hours compared with 6.5 minutes for theintravenous infusion over 5-7 minutes. In this study, intravenousibuprofen (IVIb) was found to be safe and well tolerated whenadministered over a period of five to seven minutes.

Example 3

In a prior study, in which pharmacokinetic samples were not obtained,IVIb (Caldolor®) dosing was up to 800 mg IVIb every six hours. Thatdosage regimen resulted in a significant and sustained reduction infever throughout the 48 hour dosing period. Since the majority of thepatients in that trial would be considered as critically ill given thedefinition in the study reported in this Example, the results of thatprior study support a dose up to 800 mg if required.

More particularly, this was a randomized, double blind,placebo-controlled study of intravenous ibuprofen in participants withsevere sepsis. Participants meeting criteria for severe sepsis syndromewere enrolled and randomized to receive either intravenous ibuprofen orglycine buffer vehicle diluted and administered in Normal Saline,Lactated Ringers, or D5W (dextrose 5% in water). Participants receivedeither Ibuprofen Injection 50 mg/mL or the placebo vehicle consisting ofa glycine buffer, both of which were administered intravenously over30-60 minutes every 6 hours for 8 doses. Participants were followed fora total of 30 days or until hospital discharge or death.

For all enrolled patients at baseline, the mean temperature was100.5±0.12 for the placebo group and 100.4±0.14 for the ibuprofentreated group. Within two hours after dosing with IVib, the ibuprofentreated group had a statistically significant lower temperature than theplacebo treated group (100.2±0.14 Placebo, 99.5±0.13 Ibuprofen,p=0.001). The difference remained significant through the 44 hourassessment; 2 hours after administration of the final dose of IVib (FIG.5). After the IVib was discontinued, no statistically significantdifferences were noted between the placebo and ibuprofen groups.

It was concluded that ibuprofen delivered intravenously at a dose of 10mg/kg (maximum 800 mg) every 6 hours for 8 doses to subjects with severesepsis does not alter 14-day or 30-day all-cause mortality nor does italter the rate of organ failure or organ failure reversal. Ibuprofendoes reduce the fever, tachycardia, tachypnea and lactic acidosisassociated with severe sepsis. Short term use of relatively high dosesof intravenous ibuprofen does not produce clinically significant sideeffects or toxicity.

Based on the data obtained in this study, along with the pharmacokineticdata obtained from the study reported in Example 2, it is surmised thatthe Cmax and AUC levels obtained for the 800 IVib dose in critically illpatients is about one/half (50%) of the Cmax and AUC obtained fornon-critically ill patients. It is further estimated that the 800 mgIVib dose will attain a mean Cmax within 80-125% of about 60 μg/ml andan (AUC)_(0-t) within 80-125% of about 94 μg.h/ml in critically illpatients. The Cmax figure is obtained by calculating one half of theCmax for the 800 mg IVib dose in non-critically ill patients (120μg/ml). The AUC is likewise obtained by calculating one half of the(AUC)_(0-t) obtained for non-critically ill patients (188 μg.h/ml).

CONCLUSION

It will be readily apparent to one of ordinary skill in the relevantarts that other suitable modifications and adaptations to the methodsand applications described herein are suitable and may be made withoutdeparting from the scope of the invention or any embodiment thereof.While the invention has been described in connection with certainembodiments, it is not intended to limit the invention to the particularforms set forth, but on the contrary, it is intended to cover suchalternatives, modifications and equivalents as may be included withinthe spirit and scope of the invention as defined by the followingclaims.

1. A method of treating pain and/or fever in critically ill patients in need thereof, comprising intravenously administering to a critically ill patient an ibuprofen pharmaceutical composition in a dose from about 400 mg to about 800 mg to attain a mean Cmax from about 25.7 to about 60 μg/ml, the critically ill patient receiving at least one treatment selected from vasopressor support and mechanical ventilation, wherein the dose of ibuprofen administered intravenously to the critically ill patient provides a Cmax and AUC which is about one-half of the Cmax and AUC obtained when the same dose is intravenously administered to a non-critically ill patient.
 2. The method of claim 1, wherein the dose of intravenous ibuprofen administered to the critically ill patient provides a Cmax and AUC which is from about 50% to about 61.2% of the Cmax and AUC for that dose of intravenous ibuprofen when administered to a non-critically ill patient.
 3. The method of claim 1, wherein the dose of intravenous ibuprofen administered to the critically ill patient is 400 mg and provides a mean Cmax within about 80% to about 125% of 25.7 μg/ml and a mean (AUC)₀₋₄ within about 80% to about 125% of 45.9 μg.h/ml.
 4. The method of claim 1, wherein the dose of intravenous ibuprofen administered to the critically ill patient is 800 mg and provides a mean Cmax within about 80% to about 125% of 60 μg/ml and a mean (AUC)₀₋₄ within about 80% to about 125% of 94 μg.h/ml.
 5. The method of claim 1, further comprising selecting a dosage interval for the critically ill patient of every 4 to 6 hours.
 6. The method of claim 1, further comprising intravenously administering a 400 mg dose of ibuprofen to a critically ill patient, and thereafter intravenously administering a dose of 800 mg ibuprofen to the critically ill patient in order to treat the patient's pain and/or fever. 